Increasing evidence supports a central role for the innate immune system in the host's response against viral infections. In particular, natural killer (NK) cells represent a critical early cytolytic effector cell subset that are able to spontaneously lyse virally infected cells without the need for prior antigen sensitization. In the context of HCV infection, a small number of studies have focused on this cell subset as these cells have been implicated in the early control of a number of viral infections, these cells are abundant within the liver, and that in addition to the direct antiviral effects of interferon(IFN)-a (used to treat the infection), IFN-a directly activates the antiviral capacity of NK cells. Furthermore, compelling epidemiologic evidence has identified a strong association between homozygosity of NK killer immunoglobulin-like receptor gene {KIR2DL3) and its ligand HLA-C alleles in the C1 family, suggesting that NK cells may truly play a central role in this antiviral protection. However the direct role of NK cells in HCV clearance still remains to be determined. Accumulating evidence suggests that chronic HCV infection is associated with the accumulation of a phenotyplcally and potentially functionally altered NK cells. However, HCV resolution occurs within the first weeks to months of HCV infection in 15-30% of infected individuals. This early control occurs at a time when the adaptive immune response is just being induced. Thus several groups have speculated that innate, including NK cells, rather than adaptive immune responses may play a major role in early containment. Thus in this proposal we aim to define the role of NK cells in acute HCV infection and to determine the NK cell immunological signatures associated with the ability to clear HCV infection. Thus we propose to first carefully phenotypically, transcriptionally, and functionally characterize NK cells in acute HCV infection among individuals that resolve compared to those that become chronically infected; to then dissect the role of the protective KIR2DL3/HLA-C1 combined genotype on NK cell clonal expansions and antiviral function; and finally to investigate how IFN-a and other IFNs may contribute to the specific expansion and functional activation of protective NK cell populations with unique antiviral properties. Elucidating the role of NK cells in the resolution of HCV infection may provide potentially novel opportunities to enhance the activity of particular NK cell populations to gain greater control over the virus and enhance HCV clearance rates.